Fluoride-containing dicarbonyl compounds such as 2-fluoro-3-oxoalkylcarboxylic acid ester are of significant importance since they serve as an intermediate material in the production of various pharmaceutical and agricultural agents.
In some of known production processes for these compounds, certain dicarbonyl compounds are subjected to direct fluorination by fluorine gas. For example, techniques disclosed in J. Org. Chem., 57, 2196 (1992), International Patent Publication WO94/10120, International Patent Publication WO95/14646, and Japanese Patent Laid-Open Publication No. Hei 9-255611 involve direct fluorination of 3-oxoalkylcarboxylic acid ester with fluorine gas to produce desired 2-fluoro-3-oxoalkylcarboxylic acid ester.
However, such direct fluorination with fluorine gas generally involves formation of radicals and it is thus difficult to selectively obtain the desired 2-fluoro-3-oxoalkylcarboxylic acid ester alone if 3-oxoalkylcarboxylic acid ester is directly fluorinated with fluorine gas. In particular, each of the above-described fluorination processes results in formation of unwanted by-products such as monofluoro, difluoro, and polyfluorinated compounds, making the final product inappropriate to be used as a material for medical or agricultural agents. Thus, each of these processes requires some measures to purify 2-fluoro-3-oxoalkylcarboxylic acid ester.
In this regard, the aforementioned literatures only describe addition of water to wash off the hydrogen fluoride by-product, followed by extraction with an organic solvent such as dichloromethane, and none of them mention any approach to selectively remove unwanted monofluoro, difluoro, and polyfluorinated by-products from the reaction mixture and to thereby efficiently purify the intended2-fluoro-3-oxoalkylcarboxylic acid ester. Thus, none of these techniques have reached an industrially ideal level.
In light of such situation, the present inventors made an attempt to separate the products from the reaction mixture containing differently fluorinated 3-oxoalkylcarboxylic acid esters by using a standard distillation technique. It has proven difficult, however, to purify the desired product since the polyfluorinated 3-oxoalkylcarboxylic acid esters, such as 2,5-difluoro-3-oxoalkylcarboxylic acid ester, are unstable when subjected to heat and can readily decompose to produce hydrogen fluoride.
Furthermore, polyfluorinated 3-oxoalkylcarboxylic acid esters, such as 2,4-difluoro-3-oxoalkylcarboxylic acid ester and 2,2,4-trifluoro-3-oxoalkylcarboxylic acid ester, in addition to their unstability toward heat, have a structure and a molecular weight similar to those of the desired 2-fluoro-3-oxoalkylcarboxylic acid ester and are therefore difficult to efficiently purify by distillation.
For these reasons, fluorinated 3-oxoalkylcarboxylic acid esters have been used to date as a material in the subsequent processes without being subjected to purification by distillation. One such example is a technique disclosed in European Patent 0440372A1 for producing triazole derivatives, compounds often used as a fungicide. In this technique, 2-fluoro-3-oxoalkylcarboxylic acid ester is reacted with amidine. When 2-fluoro-3-oxoalkylcarboxylic acid ester containing significant amounts of by-products is used as a material for the reaction, not only is the purity of the product reduced, but compounds of unknown structure are also formed. This considerably limits the conditions for the reaction and adds to the difficulty in producing the desired product.
Accordingly, it is an objective of the present invention to provide a novel process for effectively producing a highly purified 2-fluoro-3-oxoalkylcarboxylic acid ester suitable for use as an intermediate material in the production of medical and agricultural agents. In this process, fluorination of 3-oxoalkylcarboxylic acid ester is carried out while formation of 2,5-difluoro-3-oxoalkylcarboxylic acid ester by-product is controlled and by-products such as 2,4-difluoro-3-oxoalkylcarboxylic acid ester and 2,2,4-trifluoro-3-oxyalkylcarboxylic acid ester are selectively removed.